Related Experiment Video

Updated: Jan 8, 2026

Synthesis and Characterization of an Aspirin-fumarate Prodrug that Inhibits NFκB Activity and Breast Cancer Stem Cells
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Synthesis and Characterization of an Aspirin-fumarate Prodrug that Inhibits NFκB Activity and Breast Cancer Stem Cells

Published on: January 18, 2017

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A Covalent Allosteric Molecular Glue Suppresses NRF2-Dependent Cancer Growth

Nilotpal Roy1, Tine Wyseure1, I-Chung Lo2

  • 1Vividion Therapeutics, San Diego, California.

Cancer Discovery
|December 19, 2025
PubMed

Insights

A new drug, VVD-065, targets the NRF2 pathway by promoting its degradation. This NRF2 inhibitor shows promise in reducing tumor growth and increasing sensitivity to cancer therapies.

Area of Science:

  • Oncology
  • Molecular Biology
  • Drug Discovery

Background:

  • The NRF2 transcription factor is crucial for cancer cell survival, promoting oxidative homeostasis and metabolic reprogramming.
  • NRF2-active tumors are often dependent on NRF2 and resistant to conventional therapies like chemotherapy and radiotherapy.

Purpose of the Study:

  • To characterize VVD-065, a novel inhibitor targeting the NRF2 pathway.
  • To elucidate the mechanism of action of VVD-065 as a first-in-class allosteric molecular glue inhibitor.

Main Methods:

  • Investigated the interaction of VVD-065 with KEAP1, specifically at Cys151.
  • Assessed the effect of VVD-065 on the KEAP1-CUL3 ubiquitin-ligase complex and NRF2 degradation.
  • Evaluated VVD-065's efficacy in inhibiting NRF2-dependent tumor growth and sensitizing cancer cells to chemo/radiotherapy.

Main Results:

  • VVD-065 covalently binds to KEAP1 Cys151, enhancing KEAP1-CUL3 complex formation and promoting NRF2 degradation.
  • Unlike previous compounds, VVD-065 stabilizes the KEAP1-CUL3 complex, contrasting with Cys151-directed compounds that destabilize it.
  • VVD-065 demonstrated inhibition of tumor growth and increased sensitivity to chemo/radiotherapy in NRF2-dependent cancers.

Conclusions:

  • VVD-065 represents a novel therapeutic strategy by targeting NRF2 degradation through an allosteric molecular glue mechanism.
  • KEAP1 Cys151 acts as a tunable regulator of NRF2 stability, with VVD-065 offering a new approach to modulate this interaction.
  • The findings support the ongoing Phase I clinical trial of VVD-065 for cancer treatment.

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